Immediate release medicinal compositions for oral use

ABSTRACT

The present invention relates to an immediate release oral pharmaceutical composition which comprises as an active ingredient calcium salt of a benzylsuccinic acid derivative represented by the formula: 
                         
or its hydrate, which is useful as an agent for the treatment of diabetes.

TECHNICAL FIELD

The present invention relates to an immediate release oralpharmaceutical composition useful as an agent for the treatment ofdiabetes.

BACKGROUND OF THE INVENTION

Calcium salt of a benzylsuccinic acid derivative (chemical name:(2S)-2-benzyl-3-(cis-hexahydro-2-iso-indolinylcarbonyl)propionic acid)represented by the formula:

or its hydrate, which is an active ingredient in the pharmaceuticalcomposition of the present invention, has a remarkable lowering actionof blood sugar and has been known as a compound useful as an agent forthe treatment of diabetes (Japanese Patent Laid-Open-No. 356459/1992).

Sulfonylurea agents (SU agents) such as glibenclamide, gliclazide andthe like which have been frequently used for the treatment of diabetestake long to exert their effects and have persisting effects for severalhours, so that it has been pointed out a problem that a risk ofhypoglycemic symptoms increases conversely. For example, when SU agentis taken at a dose of sufficiently suppressing postprandialhyperglycemia, a problem that hypoglycemia is caused between meals cannot be avoided. However, since effects of the present compound areshortly persistent, it is expected as a therapeutic agent forhyperglycemia which corrects only postprandial hyperglycemic conditionwithout causing hypoglycemic condition between meals.

Rapid absorption after taking a drug in addition to early excretion ofan active component from blood is required to correct only postprandialhyperglycemic condition without causing hypoglycemic condition betweenmeals. Thus, development of immediate release preparations is needed inpostprandial hyperglycemia treatment, wherein disintegration of thepharmaceutical composition and dissolution of the active ingredient areexcellent. Generally, it is necessary for immediate release preparationsto usually have an ability of about 75% or more drug release (drugdissolution) within 20 minutes after taking the drug (Iyakuhin noKaihatsu [Development of medicines] Vol. 11, pp. 65–77, published byHirokawa Shoten). It is concerned that the present compound isproblematic in dissolution since it is poorly soluble in water.Therefore, in order to solve the problem, early development of excellentimmediate release preparations has been greatly desired.

DISCLOSURE OF THE INVENTION

The present invention relates to an immediate release oralpharmaceutical composition which comprises as an active ingredientcalcium salt of a benzylsuccinic acid derivative represented by theformula:

or its hydrate.

The invention relates to an immediate release oral pharmaceuticalcomposition which comprises as an active ingredient calcium salt of thebenzylsuccinic acid derivative represented by the above formula (I) orits hydrate, characterized by comprising at least silicon dioxide.

The invention relates to an immediate release oral pharmaceuticalcomposition which comprises as an active ingredient calcium salt of thebenzylsuccinic acid derivative represented by the above formula (I) orits hydrate, characterized by comprising at least partly pregelatinizedstarch.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing a dissolution of various tablets described inExamples 1 and 2 and in Reference Example 1 in which dihydrate ofcalcium salt of the benzylsuccinic acid derivative of the above formula(I) is an active ingredient. The vertical and the horizontal axes denotepercents of dissolution (%) of the active ingredient and time periods(minute) passed after the start of the tests, respectively.

FIG. 2 is a graph showing a dissolution of various tablets described inExamples 3 to 6 and in Reference Examples 2 to 9 in which dihydrate ofcalcium salt of the benzylsuccinic acid derivative of the above formula(I) is an active ingredient. The vertical and the horizontal axes denotepercents of dissolution (%) of the active ingredient and time periods(minute) passed after the start of the tests, respectively.

BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors have intensively studied to find immediate releaseoral pharmaceutical compositions comprising as an active ingredientcalcium salt of the benzylsuccinic acid derivative represented by theabove formula (I) or its hydrate, which have excellent disintegrationand dissolution and are therefore useful as agents for the treatment ofdiabetes. As a result, it was advantageously found that pharmaceuticalcompositions prepared by adding at least silicon dioxide or partlypregelatinized starch thereto enhance the disintegration and improveremarkably the dissolution, and thereby the present invention has beencompleted.

In immediate release oral pharmaceutical compositions comprising anactive ingredient calcium salt of the benzylsuccinic acid derivativerepresented by the above formula (I) or its hydrate, even when tabletsare prepared according to a dry method (direct compressing method), bywhich good disintegration is generally obtained, using disintegrantsusually used such as sodium carboxymethyl starch and low substitutedhydroxypropylcellulose, no preparations having good dissolution wereobtained. The preparations obtained delayed the dissolution and haveabnormally low percentages of dissolution. However, when the tabletswere prepared by adding silicon dioxide, which is usually used as alubricant, extremely excellent dissolution was surprisingly observed.For example, rapid dissolution was observed just after the start of thedissolution test using first fluid of the Japanese Pharmacopoeia, and amaximum dissolution rate was also extremely high.

Moreover, even when the tablets were prepared according to a wet method(wet granule-compressing method), which is generally inferior indisintegration, the silicon dioxide-added preparation exhibitedsurprisingly higher dissolution efficiency compared to the preparationsin which sodium carboxymethyl starch or low substitutedhydroxypropylcellulose, which is usually used as a disintegrant, wasadded. For example, rapid dissolution was observed just after the startof the dissolution test using first fluid of the Japanese Pharmacopoeia,and a maximum dissolution rate was also extremely high. Furthermore,when tablets were prepared according to the wet methods, the tablets inwhich sodium carboxymethyl starch or low substitutedhydroxypropylcellulose, which is usually used as a disintegrant, wasadded were not satisfied because the dissolution rates were still loweven after considerable time periods passed, and particular differenceswere observed in dissolution. On the contrary, when tablets wereprepared according to the wet method employing the addition of partlypregelatinized starch as a disintegrant, good dissolution was observedas in the case with the addition of silicon dioxide. The preparation inwhich carmellose was added as a disintegrant exhibited high dissolutionefficiency as well as the pharmaceutical composition of the presentinvention, but it turned the color of the preparation into pale yellowdue to incompatible combination with the calcium salt of thebenzylsuccinic acid derivative represented by the above formula (I) asthe active ingredient. In addition, it was undesirable because itsstability is not good due to decomposition of the active ingredient.

That is, the present invention relates to an immediate release oralpharmaceutical composition which comprises as an active ingredientcalcium salt of the benzylsuccinic acid derivative represented by theabove formula (I) or its hydrate, characterized by comprising at leastsilicon dioxide or partly pregelatinized starch, wherein it hasremarkable disintegration and dissolution of the active ingredientwithout incompatible combination with calcium salt of the benzylsuccinicacid derivative represented by the above formula (I) and is excellent ina long term storage.

The calcium salt of the benzylsuccinic acid derivative represented bythe above formula (I) or its hydrate comprising as an active ingredientin the present invention can be prepared by the methods described in thereferences, similar methods thereto or the like (for example, JapanesePatent Laid-Open No. 356459/1992).

Examples of silicon dioxide used for the present invention can include,but are not limited to, light anhydrous silicic acid, hydrated silicondioxide and the like. The amount of silicon dioxide to be added is notlimited but the blending from 0.5 to 5% by weight based on the wholepreparation is sufficient.

As partly pregelatinized starch used for the present invention, variousdegrees of pregelatinized starch can be used. For example, such partlypregelatinized starches include a commercially available partlypregelatinized starch [PCS (trademark)]. The amount of partlygelatinized starch to be added is not limited but the blending from 5 to20% by weight based on the whole preparation is sufficient.

The oral pharmaceutical compositions of the present invention can applyfor various formulations, and typical formulations can include granules,fine granules, powders, tablets and capsules.

For example, granules, fine granules and powders can be prepared byconventional methods. Tablets can be prepared using granules or finegranules by conventional methods, or by directly granulating accordingto a dry method (direct compressing method) by conventional methods.Capsules can be prepared by directly filling granules, fine granules ormixed powders in the capsules by conventional methods.

When the pharmaceutical compositions of the present invention areprepared, suitable additives for each preparation such as diluents,binders, surfactants, lubricants, glidants, coating materials,plasticizers, coloring agents, flavoring agents and the like can befurther used as occasion demands. These additives are those which areusually used pharmaceutically, and any of them can be used so long asthey do not affect adversely on dissolution of and combination with thecalcium salt of the benzylsuccinic acid derivative represented by theabove formula (I) or its hydrate.

Diluents can include, for example, cellulose or cellulose derivativessuch as microcrystalline cellulose and the like; starch or starchderivatives such as corn starch, wheat starch, cyclodextrin and thelike; sugar or sugar alcohol such as lactose, D-mannitol and the like;and inorganic diluents such as dried aluminum hydroxide gel,precipitated calcium carbonate, magnesium aluminometasilicate, dibasiccalcium phosphate and the like.

Binders can include, for example, hydroxypropylcellulose,methylcellulose, hydroxypropylmethylcellulose, povidone, dextrin,pullulane, hydroxypropyl starch, polyvinyl alcohol, scacia, agar,gelatin, tragacanth, macrogol and the like.

Surfactants can include, for example, sucrose esters of fatty acids,polyoxyl stearate, polyoxyethylene hydrogenated castor oil,polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitantrioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitanmonolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate,lauromacrogol and the like.

Lubricants can include, for example, stearic acid, calcium stearate,magnesium stearate, talc and the like.

Glidants can include, for example, dried aluminium hydroxide gel,magnesium silicate and the like.

Coating materials can include, for example, hydroxypropylmethylcellulose2910, aminoalkyl methacrylate copolymer E, polyvinylacetaldiethylaminoacetate, macrogol 6000, titanium oxide and the like.

Plasticizers can include, for example, triethyl citrate, triacetin,macrogol 6000 and the like.

The pharmaceutical compositions of the present invention are extremelystable, since neither change in its appearance and dissolution rate nordecomposition of its active ingredient is observed even after placingfor 1 week under a severe condition of high temperature and humidity.

The contents of the present invention are further described in detail bythe following Reference Examples, Examples and Test Examples, but thepresent invention is not limited thereto.

REFERENCE EXAMPLE 1

Active component  5.0 mg Microcrystalline cellulose 27.5 mg Lactose 28.7mg Corn starch 10.0 mg Low substitued hydroxypropylcellulose  3.0 mgCalcium stearate  0.8 mg [Total] 75.0 mg

After 412.5 g of microcrystalline cellulose, 430.5 g of lactose, 150.0 gof corn starch, 45.0 g of low substitued hydroxypropylcellulose (brandname: L-HPC/LH-11, produced by Shin-Etsu Chemical Co., Ltd.) and 12.0 gof calcium stearate were mixed with 75.0 g of dihydrate of calcium saltof the benzylsuccinic acid derivative represented by the formula (I)(active component), the mixture was compressed with a pressure of 700 kgusing 6 mm diameter round-faced (5 R) punch to prepare tablets of theabove composition.

REFERENCE EXAMPLE 2

Active component 22.0 mg Lactose 56.0 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Carmellose  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8mg 

After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g of microcrystallinecellulose and 0.8 g of carmellose (brand name; NS-300 (trademark),produced by Gotoku Yakuhin Co., Ltd.) were mixed with 2.2 g of dihydrateof calcium salt of the benzylsuccinic acid derivative represented by theformula (I) (active component), 4 g of an aqueous solution of 6% byweight of hydroxypropylcellulose (0.24 g as hydroxypropylcellulose) wasadded thereto. The mixture was granulated in a mortar, and the granuleswere passed through screen after drying in a shell dryer to yieldgranules of 30 mesh (500 μm) or less. Calcium stearate was mixed to thegranules to be at 0.95%, and the mixture was compressed with a pressureof 500 kg using 7 mm diameter round-faced (9.5 R) punch to preparetablets of the above composition.

REFERENCE EXAMPLE 3

Active component 22.0 mg Lactose 56.0 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Sodium carboxymethyl starch  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8mg 

After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g of microcrystallinecellulose and 0.8 g of sodium carboxymethyl cellulose (brand name:Primogel [trademark], produced by Matsutani Chemical Co., Ltd.) weremixed with 2.2 g of dihydrate of calcium salt of the benzylsuccinic acidderivative represented by the formula (I) (active component), 4 g of anaqueous solution of 6% by weight of hydroxypropylcellulose (0.24 g ashydroxypropylcellulose) was added thereto. The mixture was granulated ina mortar, and the granules were passed through screen after drying in ashell dryer to yield granules of 30 mesh (500 μm) or less. Calciumstearate was mixed to the granules to be at 0.95%, and the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5 R) punch to prepare tablets of the above composition.

REFERENCE EXAMPLE 4

Active component 22.0 mg Lactose 56.0 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Low substitued hydroxypropylcellulose 8.0 mg Hydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total]126.8 mg 

After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g of microcrystallinecellulose and 0.8 g of low substitued hydroxypropylcellulose (brandname; L-HPC/LH-11, produced by Shin-Etsu Chemical Co., Ltd.) were mixedwith 2.2 g of dihydrate of calcium salt of the benzylsuccinic acidderivative represented by the formula (I) (active component), 4 g of anaqueous solution of 6% by weight of hydroxypropylcellulose (0.24 g ashydroxypropylcellulose) was added thereto. The mixture was granulated ina mortar, and the granules were passed through screen after drying in ashell dryer to yield granules of 30 mesh (500 μm) or less. Calciumstearate was mixed to the granules to be at 0.95%, and the mixtre wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5 R) punch to prepare tablets of the above composition.

REFERENCE EXAMPLE 5

Active component 22.0 mg Lactose 56.0 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Low substitued hydroxypropylcellulose 8.0 mg Hydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total]126.8 mg 

After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g of microcrystallinecellulose and 0.8 g of Low substitued hydroxypropylcellulose (brandname; L-HPC/LH-22, produced by Shin-Etsu Chemical Co., Ltd.) were mixedwith 2.2 g of dihydrate of calcium salt of the benzylsuccinic acidderivative represented by the formula (I) (active component), 4 g of anaqueous solution of 6% by weight of hydroxypropylcellulose (0.24 g ashydroxypropylcellulose) was added thereto. The mixture was granulated ina mortar, and the granules were passed through screen after drying in ashell dryer to yield granules of 30 mesh (500 μm) or less. Calciumstearate was mixed to the granules to be at 0.95%, and the mixture wascopressed with a pressure of 500 kg using 7 mm diameter round-faced (9.5R) punch to prepare tablets of the above composition.

REFERENCE EXAMPLE 6

Active component 22.0 mg Lactose 56.0 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Partly pregelatinized starch  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8mg 

After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g of microcrystallinecellulose, 0.8 g of partly pregelatinized starch (brand name: PCS[trademark], produced by Asahi Kasei Co., Ltd.), 0.24 g ofhydroxypropylcellulose and 0.12 g of calcium stearate were mixed with2.2 g of dihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5 R) punch to prepare tablets of the above composition.

REFERENCE EXAMPLE 7

Active component 22.0 mg Lactose 56.0 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Sodium carboxymethyl starch  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8mg 

After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g of microcrystallinecellulose, 0.8 g of sodium carboxymethyl cellulose (brand name: Primogel[trademark], produced by Matsutani Chemical Co., Ltd.), 0.24 g ofhydroxypropylcellulose and 1.2 g of calcium stearate were mixed with 2.2g of dihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5 R) punch to prepare tablets of the above composition.

REFERENCE EXAMPLE 8

Active component 22.0 mg Lactose 56.0 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Low substitued hydroxypropylcellulose 8.0 mg Hydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total]126.8 mg 

After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g of microcrystallinecellulose, 0.8 g of low substitued hydroxypropylcellulose (brand name;L--HPC/LH-11, produced by Shin-Etsu Chemical Co., Ltd.), 0.24 g ofhydroxypropylcellulose and 0.12 g of calcium stearate were mixed with2.2 g of dihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5 R) punch to prepare tablets of the above composition.

REFERENCE EXAMPLE 9

Active component 22.0 mg Lactose 56.0 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Low substitued hydroxypropylcellulose 8.0 mg Hydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total]126.8 mg 

After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g of microcrystallinecellulose, 0.8 g of low substitued hydroxypropylcellulose (brand name;L-HPC/LH-22, produced by Shin-Etsu Chemical Co., Ltd.), 0.24 g ofhydroxypropylcellulose and 0.12 g of calcium stearate were mixed with2.2 g of dihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5 R) punch to prepare tablets of the above composition.

EXAMPLE 1

Active component  5.0 mg Microcrystalline cellulose 27.5 mg Lactose 27.9mg Corn starch 10.0 mg Low substitued hydroxypropylcellulose  3.0 mgCalcium stearate  0.8 mg Light anhydrous silicic acid  0.8 mg [Total]75.0 mg

After 275.0 g of microcrystalline cellulose, 279.0 g of lactose, 100.0 gof corn starch, 30.0 g of low substitued hydroxypropylcellulose (brandname: L-HPC/LH-11, produced by Shin-Etsu Chemical Co., Ltd.), 8.0 g ofcalcium stearate and 8.0 g of light anhydrous silicic acid (brand name:Adsolider [trademark] 101, produced by Freund Industrial Co., Ltd.) weremixed with 50.0 g of dihydrate of calcium salt of the benzylsuccinicacid derivative represented by the formula (I) (active component), themixture was compressed with a pressure of about 700 kg by a tablettingmachine using 6 mm diameter round-faced (5 R) punch to prepare tabletsof the above composition.

EXAMPLE 2

Active component  5.0 mg Microcrystalline cellulose 27.5 mg Lactose 27.3mg Corn starch 10.0 mg Low substitued hydroxypropylcellulose  3.0 mgCalcium stearate  0.8 mg Light anhydrous silicic acid  1.4 mg [Total]75.0 mg

After 275.0 g of microcrystalline cellulose, 273.0 g of lactose, 100.0 gof corn starch, 30.0 g of low substitued hydroxypropylcellulose (brandname: L-HPC/LH-11, produced by Shin-Etsu Chemical Co., Ltd.), 8.0 g ofcalcium stearate and 14.0 g of light anhydrous silicic acid (brand name:Adsolider [trademark] 101, produced by Freund Industrial Co., Ltd.) weremixed with 50.0 g of dihydrate of calcium salt of the benzylsuccinicacid derivative represented by the formula (I) (active component), themixture was compressed with a pressure of about 700 kg by a tablettingmachine using 6 mm diameter round-faced (5 R) punch to prepare tabletsof the above composition.

EXAMPLE 3

Active component 22.0 mg Lactate 56.0 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Partly pregelatinized starch  8.0 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8mg 

After 5.6 g of lactose, 2.4 g of corn starch, 1.32 g of microcrystallinecellulose and 0.8 g of partly pregelatinized starch (brand name: PCS[trademark], produced by Asahi Kasei Co., Ltd.) were mixed with 2.2 g ofdihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), 4 g of an aqueoussolution of 6% by weight of hydroxypropylcellulose (0.24 g ashydroxypropylcellulose) was added thereto. The mixture was granulated ina mortar, and the granules were passed through screen after drying in ashell dryer to yield granules of 30 mesh (500 μm) or less. Calciumstearate was mixed to the granules to be at 0.95%, and the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5 R) punch to prepare tablets of the above composition.

EXAMPLE 4

Active component 22.0 mg Lactose 60.7 mg Corn starch 26.0 mgMicrocrystalline cellulose 13.2 mg Light anhydrous silicic acid  1.3 mgHydroxypropylcellulose  2.4 mg Calcium stearate  1.2 mg [Total] 126.8mg 

After 6.07 g of lactose, 2.6 g of corn starch, 1.32 g ofmicrocrystalline cellulose and 0.13 g of light anhydrous silicic acid(brand name: Adsolider [trademark] 101, produced by Freund IndustrialCo., Ltd.) were mixed with 2.2 g of dihydrate of calcium salt of thebenzylsuccinic acid derivative represented by the formula (I) (activecomponent), 4 g of an aqueous solution of 6% by weight ofhydroxypropylcellulose (0.24 g as hydroxypropylcellulose) was addedthereto. The mixture was granulated in a mortar, and the granules werepassed through screen after drying in a shell dryer to yield granules of30 mesh (500 μm) or less. Calcium stearate was mixed to the granules tobe at 0.95%, and the mixture was compressed with a pressure of 500 kgusing 7 mm diameter round-faced (9.5 R) punch to prepare tablets of theabove composition.

EXAMPLE 5

Active component 22.0 mg Lactose 54.7 mg Corn starch 24.0 mgMicrocrystalline cellulose 13.2 mg Partly pregelatinized starch  8.0 mgLight anhydrous silicic acid  1.3 mg Hydroxypropylcellulose  2.4 mgCalcium stearate  1.2 mg [Total] 126.8 mg 

After 5.47 g of lactose, 2.4 g of corn starch, 1.32 g ofmicrocrystalline cellulose, 0.8 g of partly pregelatinized starch (brandname: PCS [trademark], produced by Asahi Kasei Co., Ltd) and 0.13 g oflight anhydrous silicic acid (brand name: Adsolider [trademark] 101,produced by Freund Industrial Co., Ltd.) were mixed with 2.2 g ofdihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I) (active component), 4 g of an aqueoussolution of 6% by weight of hydroxypropylcellulose (0.24 g ashydroxypropylcellulose) was added thereto. The mixture was granulated ina mortar, and the granules were passed through screen after drying in ashell dryer to yield granules of 30 mesh (500 μm) or less. Calciumstearate was mixed to the granules to be at 0.95%, and the mixture wascompressed with a pressure of 500 kg using 7 mm diameter round-faced(9.5 R) punch to prepare tablets of the above composition.

EXAMPLE 6

Active component 22.0 mg Lactose 56.9 mg Corn starch 24.4 mgMicrocrystalline cellulose 14.0 mg Partly pregelatinized starch  9.0 mgHydroxypropylcellulose  2.5 mg Calcium stearate  1.2 mg [Total] 130.0mg 

After 569 g of lactose, 244 g of corn starch, 140 g of microcrystallinecellulose and 90 g of partly gelatinized starch (brand name: PCS[trademark], Asahi Kasei Co., Ltd) were mixed with 2.2 g of dihydrate ofcalcium salt of the benzylsuccinic acid derivative represented by theformula (I) (active component), 416.7 g of an aqueous solution of 6% byweight of hydroxypropylcellulose (25 g as hydroxypropylcellulose) wasadded thereto. The mixture was granulated in a high shear mixer. Thegranules were dried using a fluidized-bed dryer and passed throughscreen to yield granules of 30 mesh (50 μm) or less. Calcium stearatewas mixed to the granules to be at 0.92%, and the mixture was tablettedby a tabletting machine with a pressure of 500 kg using 7 mm diameterround-faced (9.5 R) punch to prepare tablets of the above composition.

TEST EXAMPLE 1

Dissolution Test (1)

For the tablets described in Examples 1 and 2 and Reference Example 1,the dissolution test (a quantitative method: HPLC, a detection wavelength: 220 nm) was carried out using 900 mL of first fluid of theJapanese Pharmacopoeia at 50 rpm according to the paddle method,apparatus 2 of the dissolution test methods of the 13th revised JapanesePharmacopoeia. From the results of these dissolution tests as shown inFIG. 1, the tablets of Examples 1 and 2 showed much more excellentdissolution than those of Reference Example 1.

TEST EXAMPLE 2

Dissolution Test (2)

For the tablets described in Examples 3 to 6 and Reference Examples 2 to9, the dissolution test (a quantitative method: UV absorbancedetermination, a detection wave length: 205 nm) was carried out using900 mL of first fluid of the Japanese Pharmacopoeia at 50 rpm accordingto the paddle method, apparatus 2 of the dissolution test methods of the13th revised Japanese Pharmacopoeia. From the results of thesedissolution tests as shown in FIG. 2, the tablets of Examples 3 to 6showed much more excellent dissolution than those of Reference Example 3to 9.

TEST EXAMPLE 3

Compatibility Test

One gram of each of the following various additives was mixed with 1 gof dihydrate of calcium salt of the benzylsuccinic acid derivativerepresented by the formula (I), and the mixture was placed for two weeksunder a condition of temperature at 60° C. and relative humidity of 80%.Then its appearance was observed.

Additives:

Partly pregelatinized starch (brand name: PCS [trademark], produced byAsahi Kasei Co., Ltd)

Carmellose (brand name: NS-300 [trademark], produced by Gotoku YakuhinCo., Ltd)

Carmellose calcium (brand name: ECG-505 [trademark], produced by GotokuYakuhin Co., Ltd)

Croscarmellose sodium (brand name: Ac-Di-Sol, produced by Asahi KaseiCo., Ltd)

Light anhydrous Silicic acid (brand name: Adsolider [trademark] 101,Freund Industrial Co., Ltd.)

The results are shown in the following Table 1. The dihydrate of calciumsalt of the benzylsuccinic acid derivative represented by the formula(I) was stable in combination with partly pregelatinized starch or lightanhydrous silicic acid, but caused an incompatible combination withcarmellose, carmellose calcium or croscarmellose sodium.

TABLE 1 Additives Appearance Partly pregelatinized starch No changeCarmellose Colored with pale yellow Carmellose calcium Colored withfaint yellow Croscarmellose sodium Colored with faint yellow Lightanhydrous silicic acid No change

TEST EXAMPLE 4

Stability Test

The tablets described in Example 3 and 4 and Reference Example 2 wereplaced for 1 week under a condition of temperature at 60° C. andrelative humidity of 80%, and then appearance of the tablets, amounts oftheir decompositions and dissolution time periods using first fluid ofthe Japanese Pharmacopoeia were examined. As the results, the tabletsdescribed in Reference Example 2 containing carmellose changed a colorof appearance into faint yellow indicating an increase ofdecompositions. However, the tablets described in Examples 3 and 4 usingrespectively partly pregelatinized starch and light anhydrous silicicacid did not detect any changes, and their dissolution time periods didnot change and consequently the tablets were extremely stable.

1. A method for controlling release of an active ingredient from an oralpharmaceutical composition comprising: combining said active ingredientwith a disintegrating agent and diluents, wherein said active ingredientcomprises a calcium salt of a benzylsuccinic acid represented by theformula:

or its hydrate, wherein said disintegrating agent comprises at least onemember selected from the group consisting of silicon dioxide and partlypregelatinized starch, and wherein said diluents comprise (a)microcrystalline cellulose, (b) lactose and (c) corn starch, and whereindisintegration of the pharmaceutical composition and dissolution of theactive ingredient are sufficient so that 75% or more of said activeingredient releases in human gastric juice within 20 minutes ofadministering said oral composition.
 2. The method of claim 1, whereinsaid disintegrating agent is silicon dioxide.
 3. The method of claim 1,wherein said disintegrating agent is partly pregelatinized starch. 4.The method of claim 2, wherein said silicon dioxide is present in anamount of 0.5 to 5% by weight based on the total weight of saidcomposition.
 5. The method of claim 3, wherein said partlypregelatinized starch is present in an amount of 5 to 20% by weightbased on the total weight of said composition.